Fueled by the decreased costs of genotyping technologies, over the last couple of years many genome-wide association studies have reported associations of genetic variants with complex diseases and traits, such as cardiovascular diseases, cancer, diabetes, and obesity. As many of these associations have been repeatedly confirmed in large studies, we can consider them putative genuine variants. However, before these genes can be put to clinical use, important questions need to be answered, including how these genes interact with the environment, how their risk differs in disease subtypes and ethnical groups, and how they impact intermediate phenotypes. To fully examine the profile or epidemiologic architecture we will comprehensively evaluate such putative genuine variants in the Women's Health Initiative (WHI) Clinical Trial (CT) (n=68,132) and Observational Study (OS) (n=93,676). The WHI is one of the most definitive, far reaching population-based trials of post-menopausal women's health ever undertaken. This large study population not only enables us to examine the population incidence for racial and ethnic subgroups and associated risks of rigorously defined, incident diseases (specific aim 1) but allows us to investigate associated risks given in-depth information on various environmental exposures and disease risk factors as well as three randomized interventions (hormone therapy; low-fat dietary modification; calcium + vitamin D supplements) (specific aim 2). The prospective and longitudinal collection of biospecimens, intermediate outcomes, and phenotypic characteristics, such as bone mineral density, hormone concentrations, breast density, or inflammation will further permit us to link genetic variants to relevant intermediate phenotypes, which will potentially provide important clues to the biological basis of the genuine associations (specific aim 3). For a variety of outcomes we will genotype within this 4-year project 72,000 participants for about 50 disease-specific putative genuine variants and 50 ancestral informative markers. Information generated from this study will be critical to determine the health impact of any given undisputable variant. Findings may also provide valuable insights into disease pathways and mechanisms, and targets for disease screening, prevention, and treatment. To facilitate a rapid utilization of these findings we will share results from this study with the scientific community and invite outside investigators to utilize the WHI resources.